Method for the preparation of 3,4-dihydroxy-5-nitrobenzaldehyde

ABSTRACT

A method for the preparation of 3,4-dihydroxy-5-nitrobenzaldehyde by reacting 4-hydroxy-3-methoxy-5-nitrobenzaldehyde with a strong nucleophilic agent which may be created by reacting an aromatic mercapto compound with a strong organic or inorganic alkali metal base such as lithium hydroxide. The reaction is performed at elevated temperatures using an aprotic polar solvent. It is preferably carried out in an inert atmosphere.

The invention relates to a new method for the preparation of3,4-dihydroxy-5-nitrobenzaldehyde, which is an intermediate in thesynthesis of several pharmaceutically important catechol compounds.

GB-A-2200109 and EP 237929 describe a method for the preparation of3,4-dihydroxy-5-nitrobenzaldehyde, in which method4-hydroxy-3-methoxy-5-nitrobenzaldehyde is refluxed in concentratedhydrobromic acid. This method has many disadvantages which make itindustrially inapplicable. For example, hydrobromic acid causes seriouscorrosion problems and results in the formation of the by-product2-bromo-3,4-dihydroxy-5-nitrobenzaldehyde and dark coloureddecomposition products which both interfere with the purification of thedesired 3,4-dihydroxy-5-nitrobenzaldehyde. The emission of the toxicgaseous by-product methyl bromide is also a serious problem.

It has now been surprisingly found that the above disadvantages may beavoided if the dealkylation reaction is performed using a strongnucleophilic reagent. Preferably, the nucleophile is thiolate anion ofan aromatic mercapto compound such as thiophenol, 2-, 3- or4-aminothiophenol, 2-, 3- or 4-thiocresol or 1- or 2-thionaphthol or2-mercaptobenzothiazole. The thiolate anion is preferably created withthe aid of a strong organic or inorganic base such as an alkali metalhydroxide, hydride or amide. Especially preferable are the lithiumbases.

It is advisable to carry out the reaction in an inert atmosphere, thuspreventing the formation of disulphide impurities. The reaction ispreferably performed in an aprotic polar solvent, such as1-methyl-2-pyrrolidinone, N,N-dimethylformamide or N,N-dimethylacetamideunder reduced or normal pressure at elevated temperature in the range ofabout 80° to 160°, most preferably about 130° C.

The reaction is very suitable for industrial production because thereagents are readily available, cheap, noncorrosive and easily handled.The solvent used can be easily recirculated and there is no emission oftoxic gases.

Hansson and Wickberg (Synthesis, No. 3, 1976, 192--192) handles with theselective dealkylation of aromatic ethers. Unlike in the presentinvention wherein the methyl group is in meta position as counted fromthe two electronegative groups (formyl and nitro) the article of Hanssonand Wickberg describes reactions wherein the demethylation is selectivein the para and especially in the orto position. Feutrill and Mirrington(Tetrahedron Letters, No 16, 1970, 1327-28) describes the demethylationof 4-bromo-3-methyl-anisole wherein the methoxy group is also in thepara position.

EXAMPLE 1

20 g of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde, 5.4 g of lithiumhydroxide, 12 ml of thiophenol and 40 ml of NMP(1-methyl-2-pyrrolidinone) were mixed for two hours at 130° C. undernitrogen atmosphere. The mixture was cooled to 90° C. and 125 ml ofwater, 40 ml of heptane and 30 ml of strong hydrochlorid acid was added.The mixture was stirred overnight at room temperature, kept for twohours at 0° C., filtered, washed with 20 ml of cold water and dried.Yield 16.52 g (88.9%), m.p. 135°-137° C.

EXAMPLE 2

15 g of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde, 4.1 g of lithiumhydroxide, 9 ml of thiophenol and 25 ml of NMP were mixed for two hoursat 130° C. under nitrogen atmosphere. The mixture was cooled to 100° C.and 50 ml of glacial acetic acid and 30 ml of concentrated hydrochloricacid were added. The mixture was stirred overnight at room temperature,kept for two hours at 0° C., filtered, washed with 20 ml of cold waterand dried. Yield 11.38 g (81.7%), m.p. 135°-137° C.

EXAMPLE 3

15 g of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde, 3.7 g of lithiumhydroxide, 13 g of 2-mercaptobenzothiazole, 40 ml of NMP and 30 ml oftoluene were refluxed with water separation for 20 hours under nitrogenatmosphere. The mixture was cooled to 80° C. and 150 ml of water and 20ml of toluene were added. After stirring for half an hour the phaseswere separated and the toluene phase discarded. To the water phase 45 mlof concentrated hydrochloric acid was added. The mixture was stirredovernight at room temperature, kept for two hours at 0° C., filtered,washed with 20 ml of cold water and dried. Yield 12.64 g (90.7%), m.p.135°-137° C.

EXAMPLE 4

150 g of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde, 280 ml of NMP, 39 g oflithium hydroxide and 90 ml of thiophenol were kept at 130° C. for threehours under reduced pressure and the distillate was collected. Themixture was cooled to 100° C., the pressure normalized and 1000 ml ofhot water and 250 ml of concentrated hydrochloric acid were added. Themixture was stirred overnight at room temperature, kept for two hours at0° C., filtered, washed with 200 ml of cold water and dried. Yield 135 g(96.9%), m.p. 135°-137° C.

We claim:
 1. A method for the preparation of3,4-dihydroxy-5-nitrobenzaldehyde comprising the reaction of4-hydroxy-3-methoxy-5-nitrobenzaldehyde in an aprotic polar solvent atthe temperature from 80° to 160° C. with the lithium salt of an aromaticmercapto compound.
 2. The method according to claim 1, wherein thearomatic mercapto compound is 2-mercaptobenzothiazole.
 3. The methodaccording to claim 1, wherein the aromatic mercapto compound isthiophenol.
 4. The method according to claim 1, wherein it is performedin an inert atmosphere.
 5. The method according to claim 1, wherein theaprotic polar solvent is 1-methyl-2-pyrrolidinone.
 6. The methodaccording to claim 1, wherein it is performed at the temperature ofabout 130° C.